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Mutations in CHMP4C cause dilated cardiomyopathy via dysregulation of autophagy
  • +14
  • wei Zhou,
  • Lu Tang,
  • Yingying Jiang,
  • xuejie li,
  • minmin sun,
  • haiyan chen,
  • jie cui,
  • shifang shan,
  • Bo Yuan,
  • shengmei qin,
  • wenqing zhu,
  • weipeng zhao,
  • Cuizhen pan ,
  • Xianghong Shu,
  • xiaolin wang,
  • Zilong Qiu,
  • Junbo Ge
wei Zhou
Fudan University
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Lu Tang
Zhongshan Hospital Fudan University
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Yingying Jiang
Zhongshan Hospital Fudan University
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xuejie li
Fudan University
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minmin sun
Fudan University
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haiyan chen
Fudan University
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jie cui
Zhongshan Hospital Fudan University
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shifang shan
Chinese Academy of Sciences Shanghai Branch
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Bo Yuan
Chinese Academy of Sciences Shanghai Branch
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shengmei qin
Zhongshan Hospital Fudan University
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wenqing zhu
Fudan University
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weipeng zhao
Zhongshan Hospital Fudan University
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Cuizhen pan
Zhongshan Hospital Fudan University
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Xianghong Shu
Zhongshan Hospital Fudan University
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xiaolin wang
Fudan University
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Zilong Qiu
Chinese Academy of Sciences Shanghai Branch
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Junbo Ge
Fudan University
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Abstract

Gene mutations have been implicated in DCM. However, due to the difficulty of clinical genetic diagnosis, additional causal genes potentially related to DCM remain to be discovered.We screened for gene mutations in more than 400 cases from families with hereditary cardiovascular disease using whole-exome sequencing and then validated the biological functions of CHMP4C mutations in zebrafish models. To further assess the mechanism of CHMP4C mutations, we determined the potential signaling pathway in a cell line.We identified via whole-exome sequencing CHMP4C variants that segregated with DCM in four families among a total of 411 families. We further validated the function of CHMP4C in heart function in zebrafish models and found that overexpression of CHMP4C variants resulted in cardiac malformation, pericardial edema and an increased heart rate, consistent with CHMP4C mutation-associated findings in DCM patients. Furthermore, mutations in CHMP4C impaired autophagy and activated apoptosis in HEK293T cells, suggesting that the molecular mechanism of CHMP4C is involved in heart development.CHMP4C is a novel candidate gene causing DCM and may play a critical role in cardiac development by regulating autophagy.